The primary goal of this supplement project is to investigate whether the gain-of-function of the longevity gene sirtuin 6 (SIRT6) protects against Alzheimer disease (AD). This Alzheimer?s- focused administrative supplement is a logical expansion and within the scope of our active parent R01 grant entitled ?SIRT6 and vascular endothelial homeostasis?. Early studies have demonstrated that SIRT6 is involved in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation, which ultimately regulate life span. My laboratory previously generated both global SIRT6 haploinsufficient and endothelium-specific SIRT6 knockout mouse models and demonstrated that SIRT6 plays a pivotal role in maintaining vascular endothelial function and limiting atherosclerosis. By working on our parent RO1 project we have recently created a humanized SIRT6 transgenic overexpression mouse model, in which human SIRT6 gene is genetically engineered in mouse ROSA26 locus in a conditionally inducible manner with the Cre/Loxp technology. Our nascent observations suggest that genetic overexpression of human SIRT6 in mice protects against endothelial dysfunction, inflammation, and atherosclerosis. Importantly, recent findings also reveal that SIRT6 expression in the brain tissues is decreased in AD mouse model and AD patients, suggesting that SIRT6 could also be a new potential therapeutic target to treat or prevent AD. However, the potential protective role of SIRT6 in AD has not been established. Based on the multifunction of SIRT6 in DNA repair, anti-inflammation and anti-aging, we hypothesized that genetic and pharmacological activation of SIRT6 protects again AD. In this proposal, we will fully utilize our novel humanized SIRT6 transgenic moue model to explore whether SIRT6 overexpression protects against the development of AD. Furthermore, the newly discovered SIRT6 activator will be exploited to test whether pharmacological SIRT6 activation alleviates AD pathologies. Collectively, the studies proposed herein provide a framework to begin defining a potential role of SIRT6 in antagonizing the amyloid plaque formation in AD. The findings resulting from these studies should help us find a treatment or way to prevent Alzheimer's and other types of dementia, and eventually translate our research advances into improved care for people with Alzheimer?s disease.